Radiopharmaceutical Therapy Targeting PSMA for Prostate Cancer - Episode 6

VISION Trial of Lutetium-177-PSMA-617 in mCRPC: Clinical Implications

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Dr Jeremie Calais reviews the VISION trial and the implications of the data in the treatment paradigm for metastatic castration-resistant prostate cancer (mCRPC).

Alicia Morgans, MD: I am curious from your perspective, if you could share with us a little about the VISION trial, which was a study that assessed lutetium-PSMA-617. Maybe talk us through the efficacy data we saw and how we should think through that in the context of the mechanism of action of this drug. If you can comment on safety as well and how the safety profile makes sense with the mechanism of action, that would be really helpful.

Jeremie Calais, MD, MSc: Starting with the mechanism of action, and from that, we can understand a bit of the efficacy and toxicity profile of the treatment. Lutetium-PSMA [prostate-specific membrane antigen] can be called also, as in the VISION trial, lutetium-PSMA-617. It can be called targeted radionuclide therapy, targeted molecular radiotherapy, and targeted radiopharmaceutical therapy. In the end, all these names mean more or less the same. What it means is that we bring to a target protein that is expressed by the diseased cells, the prostate cancer cells, and we bring a radioactive drug, or a radiopharmaceutical, to deliver a radionuclide that emits some beta radiation to induce cell damage in the surrounding area where it has been emitted to these prostate cancers that express the target. That’s why we call it molecular radiotherapy. This is injected into the blood. Of course, it’s a much higher level of radiation than what is being used for diagnostic purposes when you use diagnostic agents. What you can guess is that the more you have target expression on a prostate cancer lesion, the more treatment will bind and go there, and the more radiation will be delivered to this prostate cancer lesion. Usually the more circling of the prostate cancer cells, the better response.

This PSMA protein is not only prostate-specific. There is a bit of that protein expression in other sites in the rest of the body, so there are some side effects. The drug will also go to other places than the prostate cancer lesion. But still, it is pretty low. Patients have a bit of expression in the salivary gland and can have some dry mouth. It’s quite frequent, but it’s never graded as severe or irreversible. In patients who have had the therapy, so far, their side effects regarding the salivary gland toxicity have been considered mild or reversible, or very rarely [more severe]. There is a bit of expression in the kidney, and you see it very nicely on the scan. Some people were concerned initially with kidney toxicity. But we are finally at the level of activity that we inject where the kidney safety profile has been established. There is not a lot of kidney toxicity unless the patient has a prior kidney disease condition, where we have a closer look. If the patient has a lot of bone metastasis, which is common, the radiation will go to the bone metastasis, that’s what we want. But it will also radiate a bit of the healthy surrounding bone marrow cells. And the bone marrow cells are the ones that produce the blood cells: red blood cells, white blood cells, and platelets. So we’ll have to monitor the blood counts closely to make sure we don’t hit too much of the bone marrow. If we see that the blood counts drop too much, we will hold until the next cycle and give patients some time to recover from this bigger bone marrow hit. We have a great story where sometimes the bone marrow function is decreased because of the tumor involvement. You treat the tumor, the tumor shrinks, and it gives more space to the bone marrow to recover and re-expand, and sometimes the bone marrow function and the blood counts increase again after treatment. So sometimes it works pretty well.

Then you have what I say are general side effects. It is injected through an IV [intravenous] line, so with any IV drug, you can have some nausea and vomiting on the day of the administration; that arises maybe in 30% of the patients. With a radiation-based treatment, very commonly you would have some fatigue on the days, the weeks following the administration, probably for 2 to 3 weeks, and then it gets better. This you can see in 50% to 60% of the patients. The last side effect I want to talk about is sometimes you have patients who have symptomatic bone metastasis disease that creates pain for the patients. And if the treatment is effective, the treatment will go there, will again create some damage, and sometimes it can increase edema, inflammation, and increase the pain transiently. Then if the treatment is effective, the pain will go away after a couple of days or weeks, showing treatment effectiveness. You would call it a bone pain flare effect or transient increase of the pain. That’s mostly what you can expect from these targeted PSMA therapies in terms of toxicity.

In terms of efficacy, in the VISION trial, it was a comparison of 2 groups. A group of patients got standard care treatment, which was basically hormonal therapies or AR [androgen receptor]-targeted therapies, vs lutetium-PSMA therapy in addition to their hormonal treatment. In that trial, lutetium-PSMA therapy led to better overall survival by the PSA [prostate-specific antigen] response rates, better imaging progression-free survival, meaning it delayed the progression on the scans. It also, very interestingly and importantly, retarded the events of what we call symptomatic skeletal events, so bone symptomatic events. It also improved the quality of life and the pain level. So on all levels, when you compare these 2 groups of patients, lutetium-PSMA showed significant improvements in the lives of these patients.

Alicia Morgans, MD: Thank you for running through that. VISION, as you mentioned earlier, included patients with metastatic CRPC [castration-resistant prostate cancer] who had had disease progression on an AR-targeted agent as well as docetaxel, at a minimum. They were randomized to the best standard of care treatment, which in many cases, as you said, was an AR-targeted agent. But it could have been pain medications, as it was for some patients, or it could have been even a steroid. This was all in combination for those patients on the treatment arm with lutetium-PSMA-617 vs that best standard of care alone. They just couldn’t have had a combination that included chemotherapy or radium or had that as the control arm because there weren’t safety data to suggest lutetium could be given concurrently there. So this was a pretty heavily pretreated patient population. There was a clear overall survival benefit. I think it is impacting our treatment landscape now that we have FDA approval of this drug. From your perspective, how is the shifting the landscape, and how are you identifying the patients who might be the best candidates for treatment?

Jeremie Calais, MD, MSc: The landscape as a nuclear medicine physician will completely change for us. As Dr Rettig introduced nicely at the beginning of the interview, prostate cancer is the most common cancer in men, so the volume of patients is very high. Many patients may need this kind of treatment at some point in their journey, and they will be referred to nuclear medicine physicians. This will be a dramatic surge for nuclear medicine physicians in the clinic. That would be a clear change in that sense. But I think it’s great to have this new treatment option to offer to patients and to have a multidisciplinary approach, where nuclear medicine physicians are integrated into the care of these patients for precision oncology, precision medicine, where you integrate imaging and this targeted radionuclide approach.

Now, this is a transition to the question you asked about how you select patients. That’s the beauty of theragnostics. Theragnostics is the combined use of a therapeutic agent and diagnostic agent that have the same molecular target. So in that case, it is PSMA. Nuclear medicine provides great tools for that because of this PSMA target on which you can bring this radioisotope to do either imaging or therapy, but on the same target. Before I talked about the use of PSMA PET [positron emission tomography] scan for showing the disease better, where it is, more sensitively, and earlier. Based on where the disease is, you can propose the best treatment plan because you see what you couldn’t see before. Now, there is a different use. When I say now, it’s for those with eligibility for lutetium-PSMA therapy. You assess the level of the target as how much it is expressed. And more importantly, you’re chasing the patients who do not have enough targets. You don’t want to give them a targeted therapy when you know that you have a lesion, obviously, that you see there that doesn’t have enough target expression, and you know will progress under this PSMA-targeted therapy. Those are the patients you’re looking for, the red flag patients, when you see that it’s probably not a good idea to use a PSMA-targeted treatment based on the PSMA-targeted imaging.

Alicia Morgans, MD: Yes, we certainly wouldn’t want to give a drug expected to have potential toxicity, though relatively tolerable, to someone who has very little expected benefit. So that makes a lot of sense. I think it’s really exciting that we have a way to select patients who are most likely to benefit from treatment. Ongoing trials are hopefully going to identify a broader spectrum of patients across the entire journey of the prostate cancer experience to allow more patients to benefit from this therapy.

Transcript edited for clarity.